b'Redefining Research & Carethe Greek words angion, meaning vessel, and from gnesis, meaning creation. While these drugs are quite effective against kidney cancers, blood vessels are important for cardiovascular health. As such, these drugs cause cardiovascular problems, including hypertension and Drs. Steven McKnight and David Russell, sometimes weakening of the heart (heartdiscoverers of HIF-2.failure). The Path to Developing a HIF-2 InhibitorResearch that Dr. Brugarolas con-ducted in Dr. Kaelins laboratory led to the 1997 preventing HIF-2 binding to HIF-1. By2018finding that HIF was not only regulated byinterfering with HIF-2 binding to HIF-1,Dr. Kevin Courtney reports the VHL, but also by mTOR (mechanisticUT Southwestern biochemist Steventhese compounds block HIF-2 action. target of rapamycin). This finding providedMcKnight, Ph.D., and molecular genet- The most promising chemicals undergo aresults of a phase 1 clinical trial a rationale for targeting mTOR in renalicist David Russell, Ph.D., report therefinement process by medicinal chem- testing PT2385 in humans. The trial cancer. Today, there are two mTOR-discovery of the EPAS1 gene. This geneists at UT Southwestern. (Scheuermannrepresents the first-in-human study blocking drugs that have been FDAcontains instructions for the HIF-2 pro- et al., Nat Chem Biol, 2013; Rogers etof a first-in-class inhibitor of HIF-2. approved (temsirolimus [Torisel] andtein. The team shows that HIF-2 bindsal., J Med Chem, 2013) The trial, which involves 51 patients, everolimus [Afinitor]). (Brugarolas et al.,Development of a first-in-class drugto another protein, HIF-1. The HIF-2shows that PT2385 is safe, well Cancer Cell, 2003) targeting HIF-2. partners function like a pair of tweezers2010 tolerated, and active against ccRCC to grab DNA. HIF-2 binds DNA at specificin humans. More than 50 percent of Discoveries Lead places to initiate the production of pro- Peloton Therapeutics is co-founded bypatients see their cancer regress or to a First-in-Class Drug For years, scientists have beenAs such, the protein class has beenteins such as VEGF. (Tian et al., Genes Dr. McKnight to develop the HIF-2- stabilize. A patient of Dr. Brugarolas The cellular protein called HIF-2 (orinterested in blocking HIF-2 to treatregarded as undruggable. Dev, 1997) blocking chemicals into drugs. Based atsees benefit for more than a year hypoxia-inducible factor-2) is regardedkidney cancer and possibly otherThis may be changing. A program ofUT Southwesterns BioCenter campus,despite prior progression on seven as the most important driver of kidneyconditions. However, HIF-2 belongs todiscovery launched at UT Southwestern2003 Peloton scientists create libraries ofdrugs. (Courtney et al.,J Clin Oncol, related compounds, ultimately identifying2018) cancer. HIF-2 is the key member of aa class of proteins, transcription factors,more than 20 years ago, which is nowThe laboratories of Richard Bruick,PT2385 and PT2977 to test in humans. family of HIF proteins activated inthat have a globular, smooth surfaceasupported by CPRIT and the SPORE, hasPh.D., and Kevin Gardner, Ph.D., uncoverA related drug, PT2399, is identified for2019kidney cancer.target too slippery for drugs to bind to.challenged these notions.aspects of the atomic blueprint oflaboratory work. HIF-2. They show how HIF-2 docksU.S. drug manufacturer Merck & Co. with HIF-1 to assemble into a functional2016 acquires Peloton Therapeutics for HIF-2 complex. They identify a cavity$1.05 billion with an additional $1.15 within the HIF-2 protein, hypothesizingDr. James Brugarolas, in collaborationbillion contingent on sales and regu-MINIMIZING KIDNEY CANCER that it may offer a foothold for a drug.with Dr. Payal Kapur, validates HIF-2latory milestones.DRUGS TOLL ON THE HEART (Erbel et al., Proc Natl Acad Sci USA,as a target in ccRCC. In experiments 2003; Yang et al., J Biol Chem, 2005;incorporating more than 250 mice2020High blood pressure commonly accompanies renal cancer when theScheuermann et al., Proc Natl Acad Scitransplanted with human kidney cancerThrough studies of biopsy samples disease is treated with blood vessel (or angiogenesis) blocking drugs.USA, 2009) (see page 67), it is shown that PT2399from patients who participated in the (i) blocks HIF-2 in ccRCC while notphase 1 clinical trial, Drs. Courtney, At UT Southwestern, patients whoFurther support is available from2007 affecting related proteins, (ii) is activePedrosa, and Brugarolas report the develop uncontrolled hypertension candoctors such as Dr. Vlad Zaha, one ofWorking with the Simmons Canceragainst 50 percent of human ccRCCidentification of drug resistance see hypertension specialists certified bythe few onco-cardiologists in NorthCenters High-Throughput Screeningtumors transplanted in mice, and (iii) hasmutations in patients, establish-the American Society of Hypertension,Texas. Onco-cardiologists are special- laboratory, Drs. Bruick and Gardnermore activity and is better tolerated thaning HIF-2 as the first known core such as Dr. Wanpen Vongpatanasin,ized cardiologists focusing onUltrasound-based imaging of the heartsunitinib (the most commonly used drugdependency of ccRCC. (Courtney et Director of the Hypertension Program.cardiovascular health in cancer patients.with the four chambers.develop a test to read out and identifyfor renal cancer treatment at the time).al., Clin Cancer Res, 2020)chemicals, among 200,000 drug-like(Chen et al., Nature, 2016; Wallace et al., molecules, that bind to the HIF-2 cavity,Cancer Res, 2016) 36 37'